tbuckley/cabot-search huggingface dataset:
CNSC-03. NEURONAL INTERMEDIATE FILAMENT (NIF) ANTIBODY POSITIVE PARANEOPLASTIC SYNDROME IN A PATIENT WITH METASTATIC NEUROENDOCRINE PANCREATIC CARCINOMA AND TREATMENT WITH IPILIMUMAB/NIVOLUMAB
Authors: Karla Mora Rodriguez, Edwin Peguero, Yolanda Pina, Jonathan Strosberg, Neha Verma, Sepideh Mokhtari
Journal: Neuro-Oncology (2022)

Abstract Immune checkpoint inhibitors, such as ipilimumab (CTL-4) and nivolumab (PD-1) have shown effectiveness in many types of neoplasia. This combination has been used as salvage immunotherapy for high grade metastatic pancreatic carcinoma. Nevertheless, severe neurologic immune-mediated adverse effects can result from the use of this treatment. We present a case of a 64-year-old woman with metastatic neuroendocrine pancreatic carcinoma with abrupt left facial and oculomotor cranial nerve palsy as well spastic tetraplegia after one dose of ipilimumab/nivolumab. She had a history of sudden onset diplopia, fever and ground-level fall a few hours after her initial dose of immunotherapy. Initial laboratory assessment showed pronounced lymphocyte predominant leukocytosis and mild chronic hyponatremia. In the following hours, she developed right mydriasis, right sided fast phase nystagmus and right central facial paralysis along with weakness and spasticity in four extremities. Neuroimaging of brain, orbits and CTL spine showed enhancement of intra-orbital and intracranial optic nerves as well chiasm, linear enhancement from C4-C7 and cauda equina, as well as abnormal signal along thoracic spinal cord and conus medullaris. Routine EEG demonstrated non-etiology specific encephalopathy. Lumbar puncture had normal opening pressure, mild pleocytosis, hyper-proteinorrhachia and normal glucose. Viral panel and cytology in the CSF were negative, and myeline basic protein was elevated. She was treated with high dose steroids which improved overall strength and CN palsies. Twenty days after initial presentation, she suddenly developed hypotension, tachypnea, and altered cognition. The patient and family opted for comfort measures only. She passed away that same day. Late report of CSF antibody panels showed positive cell-based assay for heavy and light chain NIF with a titer of 1:512. This case emphasizes the importance of recognition of anti-body mediated paraneoplastic syndromes in patients treated with immunotherapy, their appropriate treatment and prognosis.
NCOG-31. ROLE OF AGE IN CSF LEAK FOLLOWING TRANSSPHENOIDAL RESECTION OF CRANIOPHARYNGIOMA: ANALYSIS OF OUTCOMES IN PEDIATRIC VERSUS ADULT POPULATION
Authors: Nolan Brown, Shane Shahrestani, Julian Gendreau
Journal: Neuro-Oncology (2022)

Abstract Postoperative cerebrospinal fluid (CSF) leak is a serious complication after surgical treatment of craniopharyngioma. The objective of this study is to analyze postoperative CSF leak rates following transsphenoidal resection of craniopharyngioma in adult versus pediatric patient populations. PRISMA guidelines were used to query the Pubmed, Web of Science, and Cochrane databases for studies of craniopharyngioma resection in adult or pediatric patients from the past three decades. The following search terms, ("craniopharyngioma") AND ("cerebrospinal fluid" OR "CSF") AND ("leak" OR "rhinorrhea") AND ("resection" OR "surgery") AND ("transsphenoidal" OR "endonasal"), were used. The primary outcome variable collected was presence of postoperative CSF leak. Pooled analyses were performed to determine the rates of CSF leak in adult and pediatric cases. In addition, a meta-analysis was performed to compare the rates of CSF leak in the adult versus pediatric cohort. Of the 21 included studies, 8 studies reported adult cases, 9 studies reported pediatric cases, and 4 studies reported both adult and pediatric cases, for a total of 468 cases. The majority of studies were level 4 evidence (90.5%, 19/21), while two studies were level 3 evidence (9.5%, 2/21). Analysis of postoperative CSF leak in adult and pediatric cases revealed rates of 29% (95% CI: 21%-39%) and 13% (95% CI: 9%-19%), respectively. Using a random-effects meta-analysis model, we found that there was no significant difference between the two cohorts (RR: 1.56; 95% CI = 0.52-4.71; P = 0.43). The present study is the first to analyze postoperative CSF leak rates in adult and pediatric patients undergoing transsphenoidal resection of craniopharyngiomas. While we found that there is no significant difference in CSF leak rates between adult and pediatric patients, further studies of higher methodological quality are warranted to provide a better understanding of complication profiles following resection of adult and pediatric craniopharyngiomas.
DNAR-04. BOTH P53 CODON 72 ARG/ARG AND PRO/ARG GENOTYPES IN GLIOBLASTOMA MULTIFORME PATIENTS HAVE A BETTER PROGNOSIS IN BEVACIZUMAB TREATMENT
Authors: Chiung-Chyi Shen
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND In glioblastoma multiforme (GBM), bevacizumab increased progression-free survival but it has failed to improve overall survival (OS) in controlled trials. This study, therefore, aimed to retrospectively analyze the polymorphisms of p53 codon 72 and the clinical characteristics of GBM specimens from Taiwanese patients. METHODS The polymorphisms of p53 codon 72 in 99 patients with GBM treated at Taichung Veterans General Hospital in Taiwan from 2007 to 2017 were analyzed using direct DNA sequencing and PCR-RFLP analysis. RESULTS We found that among these GBM patients, the polymorphisms of p53 codon 72 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Pro genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone. CONCLUSIONS This pilot study suggests that both the Arg/Arg and Arg/Pro genotypes of p53 codon 72 polymorphism may have value as independent prognostic or predictive parameters for bevacizumab treatment response and failure. Relatedly, the results of the study further demonstrate the utility of stratifying GBM patientsaccording to bevacizumab sensitivity.
BIOM-65. SAFE MAXIMAL RESECTION OF IDH-WILDTYPE GLIOBLASTOMA WITH TUMOR-FREE MOLECULAR MARGIN RESULTS IN PROLONGED PROGRESSION-FREE SURVIVAL
Authors: Ganesh Shankar, Elie Massaad, Joseph Bradley, Jochen Lennerz, Jorg Dietrich, Bryan Choi, Brian Nahed, William Curry, Tracy Batchelor, Bob Carter, Daniel Cahill
Journal: Neuro-Oncology (2022)

Abstract Purpose Although maximal resection of wild-type GBM tumors is associated with longer survival, the association of genomic alterations with the ability to resect disease has not been elucidated. This study aimed to determine whether certain molecular alterations are less amenable to surgical resection and whether achieving a surgical margin devoid of tumor cell burden provides a clinical benefit. Methods Molecular profiling of 148 consecutive tumor samples from newly diagnosed patients with IDH-WT GBM SNaPshot genotyping, and methylation-specific PCR for MGMT promoter methylation. The association of alterations with residual volume and progression-free survival was evaluated in regression analyses. We prospectively investigated the impact of TERTp status at the surgical margin on progression-free survival (PFS) in 47 patients. PFS and overall survival (OS) were evaluated with the log-rank test and Cox regression models.Results Overall, 148 patients (91 men [61.5%], median age, 62.5 years [range 56–70 years] had maximally safe surgery. The median follow-up duration was 18 months (IQR, 4-32 months). The rate of PFS was significantly lower in MGMT promoter unmethylated IDH-WT GBM amenable to resection with residual volume &amp;gt;4.9cc (hazard ratio [HR], 2.35; 95% CI, 1.44-3.84; P=.005). Gene amplification (PDGFRA, KIT, KDR) on 4q12 and TP53 and RB1 mutations were associated with greater RV. Prospective trial revealed median PFS for tumors with TERTp mutations in the surgical margin was 10.1 months while tumors with undetectable TERTp mutations in the margin did not progress (median follow-up 8.1 months, IQR 1.6-14.6). Surgical tumor margins devoid of TERTp mutations were associated with significantly different probability of PFS (0.23; 95%CI 0.15-0.43; P&amp;lt; 0.01)Conclusion In conclusion, 4q12 amplification (KDR/PDGFRA/KIT) and tumor suppressor gene alterations (RB1, TP53) were associated with greater residual volume. Tumor-free margins defined spatially by intraoperative navigation as assessed by quantifying TERTp mutation allelic fraction was correlated with prolonged PFS.
EXTH-68. ONCOMAGNETIC TREATMENT SELECTIVELY KILLS GLIOMA CANCER CELLS BY INDUCING OXIDATIVE STRESS AND DNA DAMAGE
Authors: Shashank Hambarde, Arvind Pandey, David Baskin, Santosh Helekar
Journal: Neuro-Oncology (2022)

Abstract A new noninvasive therapeutic device developed in our laboratory called the Oncomagnetic device provides a novel approach to glioblastoma (GBM) treatment. It involves repeated stimulation with oscillating magnetic fields (sOMF) produced by spinning permanent magnets. It is technologically and mechanistically distinct from the Optune® device approved by the FDA for the treatment of newly diagnosed and recurrent GBM. Use of this device in one end-stage GBM patient reversed the progression of his recurrent tumor causing &amp;gt;30% reduction in its contrast-enhanced volume within 4 weeks of treatment. Mice with implanted mouse glioma cells in their brains also showed marked reduction in tumor size, increased survival (p&amp;lt; 0.05, n = 10) and higher DNA damage (g-H2AX foci) after sOMF treatment with a whole-body stimulation method developed by us. Normal mice exposed to sOMF for 4 months had no adverse effects on the brain and other organs. In-vitro, sOMF markedly increased reactive oxygen species (ROS) levels in cancer cells leading to the selective death of these cells, while sparing normal neurons and astrocytes. Detection of g-H2AX and 53BP1 foci showed that sOMF caused significant DNA damage in GBM cells and diffuse intrinsic pontine glioma (DIPG) cells but not in normal astroglial SVGp12 cells. Furthermore, sOMF exposure for just 2 h resulted in &amp;gt;40% loss of surviving GBM and DIPG cell colonies detected by clonogenic cell survival assay, similar to that produced by 2 Gy radiation dose. This loss was rescued by the antioxidant Trolox. These results indicate that sOMF stimulation has high anticancer potency comparable to low dose radiation therapy at the cellular level with an underlying mechanism of action that is substantially different from that proposed for Optune® TTF.
STEM-12. DISCOVERY THE ORIGIN-CELLS FOR HUMAN GLIOBLASTOMA GENESIS IN SUBVENTRICULAR ZONE
Authors: Seon-Jin Yoon, Ran Joo Choi, Yoojung Oh, Se-Young Cho, Hyun Jung Kim, Joo Ho Lee, Eunchae Yeo, Jihwan Yoo, Ju Hyung Moon, Eui Hyun Kim, Se Hoon Kim, Huyn Seok Kim, Jong Hee Chang, Sangwoo Kim, Hoon Kim, Jeong Ho Lee, Seok-Gu Kang
Journal: Neuro-Oncology (2022)

Abstract Human glioblastoma (GBM), originating from the subventricular zone (SVZ), occurs due to molecular disruptions in chromosomes. Most GBM tissues exhibit definitive chromosomal patterns: copy-number-variations (CNV) in chromosome 7 (gain) and 10 (loss), known as the earliest molecular events. Herein, we hypothesised that the origin-cells in SVZ of GBM patients can provide clues regarding these chromosomal alterations. We compared bulk RNA sequencing (RNAseq) data of GBM tumor tissue (n=126), tumour free GBM SVZ (n=40), and tumor-free control SVZ of non-glial tumor (n=9). Paired single-cell-level RNAseq samples of tumor free GBM SVZ (n=7) and GBM tumor tissue (n=10), were done to see cell specific CNVs. Using human SVZ and GBM samples as a background, we generated origin-cell and origin-cell-derived tumour cell using CRISPR/Cas9. In this work, we identified two GBM-origin-cell types with stem-cell signatures during single-cell level analyses of 60 SVZ tissue samples obtained from tumor-free regions of GBM patients. Furthermore, single-cell level analysis revealed that two origin-cell types in SVZ harbor ongoing patterns of CNV alterations. Among the origin-cells found in the SVZ of GBM patients, NO-like cells showed neural progenitor plus oligodendrocyte progenitor (NO) signature, while AN-like cells showed astrocyte plus neural stem cell (AN) signature. For the interconnectedness, we subjected single-cell-level RNA-seq data to ligand-receptor connection analysis. In the stem cell mode, NO-like cells was connected to AN-like cells in SVZ samples and while in the tumor samples, cycling cell was connected to AN-like cells. NO-like cells was common in TERT promoter wildtype GBM and AN-like cells was more common in TERT promoter mutant GBM. CRISPR/Cas9 models revealed accumulation copy-number alterations from non-tumorigenic origin-cells to tumor cells. These two origin-cells (NO-like cells and AN-like cells) derived from the SVZ of the adult human brain will facilitate the understanding of GBM genesis and development of potential novel therapeutic targets.
SURG-38. ASSESSING THE ROLE OF FRAILTY IN CRANIAL NEUROSURGERY FOR PRIMARY CNS NEOPLASMS IN THE GERIATRIC POPULATION: SEVEN YEAR RETROSPECTIVE ANALYSIS USING THE NATIONWIDE READMISSION DATABASE
Authors: Shane Shahrestani, Nolan Brown, Rohin Singh, Julian Gendreau
Journal: Neuro-Oncology (2022)

Abstract Frailty is a clinical state of increased vulnerability due to age-associated decline and has been well established as a perioperative risk factor. Yet, literature describing the effects of frailty on short- and long-term complications in geriatric patients is limited. In this study, the authors evaluate the effects of frailty in geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm. For this purpose, we conducted a retrospective cohort study between 2010 and 2017 by using the Nationwide Readmission Database. Demographics and frailty were queried at primary admission, and readmissions were analyzed at 30-, 90-, and 180-day intervals. Nearest-neighbor propensity score matching for demographics was implemented to identify nonfrail control patients with similar diagnoses and procedures. The analysis used Welch two-sample t-tests for continuous variables and chi-square test with odds ratios. A total of 6713 frail patients and 6629 nonfrail patients were identified at primary admission. At primary admission, frail geriatric patients undergoing cranial neurosurgery had increased odds of developing acute posthemorrhagic anemia (OR 1.56, 95% CI 1.23-1.98; p = 0.00020); acute infection (OR 3.16, 95% CI 1.70-6.36; p = 0.00022); acute kidney injury (OR 1.32, 95% CI 1.07-1.62; p = 0.0088); urinary tract infection prior to discharge (OR 1.97, 95% CI 1.71-2.29; p &amp;lt; 0.0001); acute postoperative cerebral infarction (OR 1.57, 95% CI 1.17-2.11; p = 0.0026); and mortality (OR 1.64, 95% CI 1.22-2.24; p = 0.0012) compared to nonfrail geriatric patients receiving the same procedure. In addition, frail patients had a significantly increased inpatient length of stay (p &amp;lt; 0.0001) and all-payer hospital cost (p &amp;lt; 0.0001) compared to nonfrail patients at primary admission. Frailty may significantly increase the risks of short-term acute complications in geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm. Long-term analysis revealed no significant difference in complications between frail and nonfrail patients.
CTNI-54. A PHASE 0/1 ‘TRIGGER’ TRIAL OF RIBOCICLIB PLUS EVEROLIMUS IN RECURRENT HIGH-GRADE GLIOMA
Authors: Nader Sanai, An-Chi Tien, Jun Jiang, Yu-Wei Chang, Chelsea Montgomery, Anita DeSantis, Yoko Fujita, Seongho Kim, Shwetal Mehta
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients. METHODS Eligible patients had recurrent HGG with (1) RB+, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations. Six patients received five days of ribociclib (400mg QD) plus everolimus (2.5mg QD) and underwent tumor resection at 2, 8 or 24 hours following the last dose. Six dose-escalation cohorts (n = 3 each) reached a dose-level of ribociclib (600mg QD) plus everolimus (70mg QW). Tumor tissue, CSF, and plasma were collected. Total and unbound drug concentrations were determined using validated LC-MS/MS methods. Tumor PD effects were compared to matched archival tissue. A PK ‘trigger’ (i.e., unbound concentration &amp;gt; 5-fold biochemical IC50) and a PD ‘trigger’ ( &amp;gt;30% decrease in both pRB and pS6) in Gd-nonenhancing tissue were set to qualify patients for expansion. RESULTS 24 patients with WHO Grade III (n = 2) and Grade IV (n = 22) gliomas were enrolled. No dose-limiting toxicities were observed. Following presurgical drug, all patients demonstrated marked decrease in Gd-enhancement on preoperative MRI. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 561 nM whereas no unbound everolimus concentrations were detected. Across all dose-levels, 57% (13/23) and 43% (10/23) of tumors demonstrated RB and S6 phosphorylation decrease, respectively. CONCLUSION In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor. Everolimus exhibits limited penetration into human glioma tissue. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients.
CTIM-34. PRELIMINARY SAFETY AND EFFICACY DATA ON TWO PATIENTS WITH RELAPSED/REFRACTORY CNS LYMPHOMA TREATED WITH EMAVUSERTIB (CA-4948) AND IBRUTINIB COMBINATION: A SUBSET ANALYSIS OF TAKEAIM LYMPHOMA TRIAL
Authors: Madiha Iqbal, Han Tun, Erel Joffe, Christian Grommes, Grzegorz Nowakowski, Matthew Lunning, Radhakrishnan Ramchandren, Chia-Cheng Li, Wanying Zhao, Elizabeth Martinez, Reinhard von Roemeling, Robert Earhart, Meaghan McMahon, Iris Isufi, Lori Leslie, Allison Rosenthal
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Emavusertib, an oral interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, targets toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathway in B-cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of NF-κB, causing inflammation and tumor growth. Emavusertib has been reported to be well tolerated and active as monotherapy in heavily pretreated relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). In a murine PDX model of primary CNS lymphoma (PCNSL), emavusertib crossed the blood-brain barrier, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, emavusertib showed in vivo anti-cancer synergy in B-cell NHL. METHODS This is an ongoing open-label trial (NCT03328078) in patients with R/R NHL. Currently, we are in the dose escalation portion of combination therapy to evaluate safety and efficacy following treatment of emavusertib at dose levels of 200 or 300mg BID with ibrutinib at full prescribed dose. As of May 6th, 2022, 13 patients have been treated with emavusertib+ibrutinib combination therapy. RESULTS Among the 13 patients, two were diagnosed with R/R PCNSL and had several prior lines of anti-cancer therapy. Emavusertib in combination with ibrutinib (560 mg daily) appeared to be well tolerated in these two subjects. One patient experienced Gr3 treatment-related adverse events (thrombocytopenia, muscle weakness, pain). The preliminary efficacy data demonstrated one CR and one SD. The patient who achieved CR after the combination therapy was originally intolerant to high-dose methotrexate based chemoimmunotherapy and did not achieve complete remission after switching to ibrutinib, providing early clinical evidence of CNS penetration and anti-tumor activity of emavusertib. CONCLUSION In R/R PCNSL, these preliminary data suggest that combination therapy has a tolerable safety profile with promising anti-cancer activity and may overcome ibrutinib resistance.
PATH-07. MULTIPLATFORM MOLECULAR ANALYSES REFINE CLASSIFICATION AND PROGNOSTICATION OF GLIOMAS ARISING IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 1
Authors: Calixto-Hope Lucas, Emily Sloan, Jangham Jung, Rohit Gupta, Jasper Wu, Harish Vasudevan, Anny Shai, Nicholas Whipple, Carol Bruggers, David Samuel, Ossama Maher, Rufei Lu, Kanish Mirchia, Daniel Sullivan, Melike Pekmezci, Tarik Tihan, Andrew Bollen, Arie Perry, Anu Banerjee, Nalin Gupta, Sabine Mueller, John de Groot, Jennifer Clarke, David Raleigh, Joanna J Phillips, Alyssa Reddy, Susan M Chang, Mitchel S Berger, Aaron Diaz, David A Solomon
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Gliomas arising in patients with neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade (LG) or high-grade (HG), and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 and epigenetic classification of these tumors remain limited. METHODS Next-generation sequencing and DNA methylation profiling was performed on gliomas from 47 NF1 patients and correlated with clinicopathologic features, treatment, and outcomes. RESULTS 30 tumors demonstrated biallelic inactivation of NF1 without additional oncogenic alterations (“molecular LG subgroup”, median age 14 yrs). The remaining 17 tumors harbored additional oncogenic alterations beyond NF1 (“molecular HG subgroup”, median age 28), most frequently CDKN2A homozygous deletion (n=13), ATRX mutation (n=8), PIK3CA or PIK3R1 mutation (n=4), and TP53 mutation (n=3). Survival analysis showed significant differences in time to progression (137 vs 11 mos, p&amp;lt; 0.0001) and median survival time (undefined vs 37 mos, p &amp;gt; 0.0001) for molecular LG versus HG subgroups. DNA methylation profiles of the molecular LG subgroup resolved into a new epigenetic cluster closest to but divergent from the three existing reference classes of sporadic pilocytic astrocytoma. DNA methylation profiles of the molecular HG subgroup demonstrated most tumors epigenetically align with either HGAP or various subclasses of IDH-wildtype GBM. CONCLUSION NF1-associated gliomas stratify into two molecular subgroups. The “molecular LG subgroup” occurs primarily during childhood, harbors biallelic NF1 inactivation only, follows a more indolent clinical course, and has a unique epigenetic signature for which we propose the terminology “pilocytic astrocytoma, arising in the setting of NF1”. The “molecular HG subgroup” occurs primarily during adulthood, harbors additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, follows a more aggressive clinical course, and is epigenetically diverse. These findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.